Inventive step of treating a subpopulation of patients in view of prior art reporting a positive phase 3 clinical trial (T 1437/21)

The European patent at issue in T 1437/21 (EP 2981271) related to the second medical use of a known drug (empagliflozin) in a subpopulation of patients. The prior art cited against the patent was the patentee's own press releases reporting the success of a phase III clinical trial of the drug in the broader patient population. The patent was found novel and inventive on the grounds that the efficacy of the drug in the claimed subpopulation could not be derived, or be reasonably expected, in view of the press releases. 

Case Background

Empagliflozin (branded as Jardiance) is marketed in the EU by Eli Lilly and Boehringer Ingelheim for the treatment of type II diabetes (EU/1/14/930). Critically, the therapeutic efficacy of empagliflozin is affected by impaired kidney function. The EU label indicates that empagliflozin is not recommended in patients with severe renal impairment as measured by estimated glomerular filtration rate (e.g. a eGFR <30 ml/min/1.73²). The drug substance is protected by a composition of matter patent and associated SPCs until 2029. 

The patent at issue in T 1437/21 was a second medical use patent for the use of empagliflozin expiring in 2034.  The patent (EP 2981271) claimed empagliflozin for use in the treatment of type 2 diabetes in a subpopulation of patients with moderate renal impairment (eGFR of 30-60 ml/min/1.73 m²).  Eight oppositions were filed against the patent. The patentee appealed the decision of the Opposition Division to revoke the patent for lack of novelty in view of a press release by the patentee reporting the success of phase 3 clinical trial of empagliflozin in type 2 diabetes with "mild, moderate and severed renal impairment". 

Novelty of a second medical use claims in a subpopulation of patients requires an unambiguous disclose of the therapeutic effect in that subpopulation

The prior art cited against the patent included various press releases from Boehringer Ingelheim and Eli Lilly announcing the positive results of a phase 3 clinical trial evaluating empagliflozin in type 2 diabetes patients with mild, moderate and severe renal impairment. The press releases announced that empagliflozin had been shown to be successful in treating type 2 diabetes in the study. 

The patentee argued that the press releases only provided a generic disclosure of empagliflozin for the treatment of type 2 diabetes patients with "mild to severe" renal impairment (i.e. eGFR of 15-90 ml/min/1.73 m²). The patent, by contrast, claimed empagliflozin for use in treating a patient subgroup  having moderate renal impairment (defined as a eGFR of 30-60 ml/min/1.73 m²). 

Kidney assessment 

The Board of Appeal agreed with the patentee that, from the press releases, the skilled person could not directly and unambiguously derive the information that empagliflozin was is effective in each of the subgroups of patients evaluated in the clinical trials (i.e. mild, moderate and severe renal impairment). The success of empagliflozin in treating patients with moderate renal impairment was therefore not found to be unambiguously disclosed by the statement in the press release of the efficacy in empagliflozin in the broader patient group having "mild to severe" renal impairment:

"the positive comments on the results from the trial expressed in the press releases [...] ('encouraged by the efficacy and safety results', 'pleased with these results for these Phase III clinical trials for empagliflozin') [...] do not provide any basis for the skilled reader to conclude that as a matter of fact the 25 mg dose must also have been effective in the patients with moderate renal impairment." (r. 3.3). 

Disagreeing with the Opposition Division, the Board of Appeal concluded that the claims directed to the treatment of a subgroup of patients with moderate renal impairment were therefore novel (r. 3.4). 

In its novelty analysis, the Board of Appeal followed the recent case law on the novelty of selection inventions which requires novelty to be assessed solely on the basis of whether there is a clear and unambiguous disclosure of the selection in the prior art, and which rejects the previous case law that such a selection must also be "purposive" in order to possess novelty (IPKat). The decision in T 1437/21 is was also in line with T 1356/21 by the same board (3.3.07) which rejected the argument that any special criteria should be applied to the novelty of second medical use selection inventions (IPKat). 

Inventive step of a second medical use claims in a subpopulation of patients in the absence of a reasonable expectation of success

Applying the problem solution approach, the Board of Appeal assessed whether the second medical use of empagliflozin in the subpopulation of patients having moderate renal impairment was inventive. The Board of Appeal first noted that the fact that it is known in the prior art that there is ongoing clinical trial for a particular medical use of drug, does not necessarily render a claim directed to the drug for that use obvious: 

"the approval of a clinical study depends on the assessment of the foreseeable risks to the participants in relation to the anticipated benefit in terms of the relevance of the findings. The approval of a clinical trial does therefore not, by way of a heuristic, imply an expected positive outcome of the treatment. Furthermore [...] the authorisation of a clinical trial does not represent a scientific advice on the development programme of the investigational product tested" (r. 4.3.1) 

In the case in question, the Board of Appeal found that the crucial issue was whether, in view of the clinical trial summaries and press releases reporting the success of the trial, the skilled person would have had a reasonable expectation that empagliflozin would be effective in treatment of diabetic patients having moderate renal impairment.

The clinical trial assessed empagliflozin  in patients with mild, moderate or severe impairment. In support of the inventive step of the claimed use of empagliflozin in patients with moderate renal impairment, the patentee cited post-published data showing empagliflozin is not effective in patients with severe renal impairment. The Board of Appeal was convinced by this evidence that efficacy of empagliflozin in patients with severe renal impairment was not expected. As such, the mere inclusion of patients with renal impairment "beyond the stage of mild renal impairment" in the clinical trial "could not by itself have provided the skilled person with a reasonable expectation of success of the treatment in these patients with moderate or severe renal impairment". In other words, a skilled person would understand that a clinical trial may be conducted in patient subgroups for which there is no reasonable expectation of success. 

Furthermore, the press release made no specific disclosure about the efficacy of empagliflozin in different subgroups of patients, and did not disclose the number of patients with moderate renal impairment included in the study. The Board of Appeal concluded that any conclusions about the efficacy of empagliflozin patients with moderate renal impairment included in the study from the press releases were therefore purely speculative and unconvincing (r. 4.3.3.).

The Board of Appeal thus concluded that in the absence of a reasonable expectation of significant efficacy of empagliflozin in the treatment of diabetic patients with moderate renal impairment the subject-matter of claim 1 as granted was not obvious to the skilled person in view of the prior art and involved an inventive step.

Final thoughts

The decision in T 1437/21 is a reminder that the novelty and inventive step of second medical use claims in Europe is always something that must be assessed on a case by case basis, taking into account the challenging nature of the disease indications involved. 

Further reading

• A novel selected sub-range is no longer required to be a “purposive selection” (Oct 2019)
• Second medical use dosage regimen claim successfully traverses both insufficiency and "obvious-to-try" attacks (T 0799/16) (March 2021)
• Make no bones about it: The "credibility test" has no place in the novelty assessment of second medical use claims (T 0558/20) (Aug 2023)
• The criteria for the novelty and inventive step of pharmaceutical selection inventions (T 1356/21) (Dec 2023)

Image credit: Midjourney